Epogen

"The U.S. Food and Drug Administration is alerting health care providers and patients of a voluntary nationwide recall of all lots of Omontys Injection by Affymax, Inc., of Palo Alto, Calif., and Takeda Pharmaceuticals Company Limited, of Deerfiel"...

Using ESAs to target a hemoglobin level of greater than 11 g/dL increases
the risk of serious adverse cardiovascular reactions and has not been shown
to provide additional benefit [see Clinical Studies]. Use caution in
patients with coexistent cardiovascular disease and stroke [see DOSAGE
AND ADMINISTRATION]. Patients with CKD and an insufficient hemoglobin
response to ESA therapy may be at even greater risk for cardiovascular reactions
and mortality than other patients. A rate of hemoglobin rise of greater than
1 g/dL over 2 weeks may contribute to these risks.

In controlled clinical trials of patients with cancer, Epogen and other
ESAs increased the risks for death and serious adverse cardiovascular reactions.
These adverse reactions included myocardial infarction and stroke.

Patients with Chronic Kidney Disease

Normal Hematocrit Study (NHS): A prospective, randomized, open-label study
of 1265 patients with chronic kidney disease on dialysis with documented evidence
of congestive heart failure or ischemic heart disease was designed to test the
hypothesis that a higher target hematocrit (Hct) would result in improved outcomes
compared with a lower target Hct. In this study, patients were randomized to
epoetin alfa treatment targeted to a maintenance hemoglobin of either 14 ±
1 g/dL or 10 ± 1 g/dL. The trial was terminated early with adverse safety
findings of higher mortality in the high hematocrit target group. Higher mortality
(35% vs. 29%) was observed for the patients randomized to a target hemoglobin
of 14 g/dL than for the patients randomized to a target hemoglobin of 10 g/dL.
For all-cause mortality, the HR=1.27; 95% CI (1.04, 1.54); p=0.018. The incidence
of nonfatal myocardial infarction, vascular access thrombosis, and other thrombotic
events was also higher in the group randomized to a target hemoglobin of 14
g/dL.

CHOIR: A randomized, prospective trial, 1432 patients with anemia due to CKD
who were not undergoing dialysis and who had not previously received epoetin
alfa therapy were randomized to epoetin alfa treatment targeting a maintenance
hemoglobin concentration of either 13.5 g/dL or 11.3 g/dL. The trial was terminated
early with adverse safety findings. A major cardiovascular event (death, myocardial
infarction, stroke, or hospitalization for congestive heart failure) occurred
in 125 of the 715 patients (18%) in the higher hemoglobin group compared to
97 of the 717 patients (14%) in the lower hemoglobin group [hazard ratio (HR)
1.34, 95% CI: 1.03, 1.74; p = 0.03].

TREAT: A randomized, double-blind, placebo-controlled, prospective trial of
4038 patients with: CKD not on dialysis (eGFR of 20 – 60 mL/min), anemia (hemoglobin
levels ≤ 11 g/dL), and type 2 diabetes mellitus, patients were randomized
to receive either darbepoetin alfa treatment or a matching placebo. Placebo
group patients also received darbepoetin alfa when their hemoglobin levels were
below 9 g/dL. The trial objectives were to demonstrate the benefit of darbepoetin
alfa treatment of the anemia to a target hemoglobin level of 13 g/dL, when compared
to a “placebo” group, by reducing the occurrence of either of two
primary endpoints: (1) a composite cardiovascular endpoint of all-cause mortality
or a specified cardiovascular event (myocardial ischemia, CHF, MI, and CVA)
or (2) a composite renal endpoint of all-cause mortality or progression to end
stage renal disease. The overall risks for each of the two primary endpoints
(the cardiovascular composite and the renal composite) were not reduced with
darbepoetin alfa treatment (see Table 1), but the risk of stroke was
increased nearly two-fold in the darbepoetin alfa -treated group versus the
placebo group: annualized stroke rate 2.1% vs. 1.1%, respectively, HR 1.92;
95% CI: 1.38, 2.68; p < 0.001. The relative risk of stroke was particularly
high in patients with a prior stroke: annualized stroke rate 5.2% in the darbepoetin
alfa- treated group and 1.9% in the placebo group, HR 3.07; 95% CI: 1.44, 6.54.
Also, among darbepoetin alfa -treated subjects with a past history of cancer,
there were more deaths due to all causes and more deaths adjudicated as due
to cancer, in comparison with the control group.

Patients with Cancer

An increased incidence of thromboembolic reactions, some serious and life-threatening,
occurred in patients with cancer treated with ESAs.

In a randomized, placebo-controlled study (Study 1 in Table 2) of 939 women with metastatic breast cancer receiving chemotherapy,
patients received either weekly epoetin alfa or placebo for up to a year. This
study was designed to show that survival was superior when epoetin alfa was
administered to prevent anemia (maintain hemoglobin levels between 12 and 14
g/dL or hematocrit between 36% and 42%). This study was terminated prematurely
when interim results demonstrated a higher mortality at 4 months (8.7% vs. 3.4%)
and a higher rate of fatal thrombotic reactions (1.1% vs. 0.2%) in the first
4 months of the study among patients treated with epoetin alfa. Based on Kaplan-Meier
estimates, at the time of study termination, the 12-month survival was lower
in the epoetin alfa group than in the placebo group (70% vs. 76%; HR 1.37, 95%
CI: 1.07, 1.75; p = 0.012).

Patients Having Surgery

An increased incidence of deep venous thrombosis (DVT) in patients receiving
epoetin alfa undergoing surgical orthopedic procedures was demonstrated [see
ADVERSE REACTIONS]. In a randomized, controlled study, 680 adult patients,
not receiving prophylactic anticoagulation and undergoing spinal surgery, were
randomized to 4 doses of 600 Units/kg epoetin alfa (7, 14, and 21 days before
surgery, and the day of surgery) and standard of care (SOC) treatment (n = 340)
or to SOC treatment alone (n = 340). A higher incidence of DVTs, determined
by either color flow duplex imaging or by clinical symptoms, was observed in
the epoetin alfa group (16 [4.7%] patients) compared with the SOC group (7 [2.1%]
patients). In addition to the 23 patients with DVTs included in the primary analysis, 19 [2.8%] patients (n = 680) experienced 1 other thrombovascular event
(TVE) each (12 [3.5%] in the epoetin alfa group and 7 [2.1%] in the SOC group).
Deep venous thrombosis prophylaxis is strongly recommended when ESAs are used
for the reduction of allogeneic RBC transfusions in surgical patients [see DOSAGE
AND ADMINISTRATION].

Increased mortality was observed in a randomized, placebo-controlled study
of Epogen in adult patients who were undergoing CABG surgery (7 deaths in 126
patients randomized to Epogen versus no deaths among 56 patients receiving placebo).
Four of these deaths occurred during the period of study drug administration
and all 4 deaths were associated with thrombotic events.

Prescribing and Distribution Program for Epogen in Patients With Cancer

In order to prescribe and/or dispense Epogen to patients with cancer and anemia
due to myelosuppressive chemotherapy, prescribers and hospitals must enroll
in and comply with the ESA APPRISE Oncology Program requirements. To enroll,
visit www.esa-apprise.com or call 1-866-284-8089 for further assistance. Additionally,
prior to each new course of Epogen in patients with cancer, prescribers and
patients must provide written acknowledgment of a discussion of the risks of
Epogen.

Decreased 3-year progression-free and overall survival
and locoregional control

Radiotherapy Alone

Study 5
Head and neck cancer
(n = 351)

≥ 15 g/dL (M)
≥ 14 g/dL (F)

Not available

Locoregional progression-free survival

Decreased 5-year locoregional progression-free and overall
survival

Study 6
Head and neck cancer
(n = 522)

14-15.5 g/dL

Not available

Locoregional disease control

Decreased locoregional disease control

No Chemotherapy or Radiotherapy

Study 7
Non-small cell lung cancer
(n = 70)

12-14 g/dL

Not available

Quality of life

Decreased overall survival

Study 8
Non-myeloid malignancy
(n = 989)

12-13 g/dL

10.6 g/dL;
9.4, 11.8 g/dL

RBC transfusions

Decreased overall survival

*Q1= 25th percentile
Q3= 75th percentile

Decreased Overall Survival

Study 1 was described in the previous section.
Mortality at 4 months (8.7% vs. 3.4%) was significantly higher in the epoetin
alfa arm. The most common investigator-attributed cause of death within the
first 4 months was disease progression; 28 of 41 deaths in the epoetin alfa
arm and 13 of 16 deaths in the placebo arm were attributed to disease progression.
Investigator-assessed time to tumor progression was not different between the
2 groups. Survival at 12 months was significantly lower in the epoetin alfa
arm (70% vs. 76%; HR 1.37, 95% CI: 1.07, 1.75; p = 0.012).

Study 7 was a multicenter, randomized, double-blind study (epoetin alfa vs.
placebo) in which patients with advanced non-small cell lung cancer receiving
only palliative radiotherapy or no active therapy were treated with epoetin
alfa to achieve and maintain hemoglobin levels between 12 and 14 g/dL. Following
an interim analysis of 70 patients (planned accrual 300 patients), a significant
difference in survival in favor of the patients in the placebo arm of the study
was observed (median survival 63 vs. 129 days; HR 1.84; p = 0.04).

Study 8 was a randomized, double-blind study (darbepoetin alfa vs. placebo)
in 989 anemic patients with active malignant disease, neither receiving nor
planning to receive chemotherapy or radiation therapy. There was no evidence
of a statistically significant reduction in proportion of patients receiving
RBC transfusions. The median survival was shorter in the darbepoetin alfa treatment
group than in the placebo group (8 months vs. 10.8 months; HR 1.30, 95% CI:
1.07, 1.57).

Decreased Progression-free Survival and Overall Survival

Study 3 was a randomized, open-label, controlled, factorial design study in
which darbepoetin alfa was administered to prevent anemia in 733 women receiving
neo-adjuvant breast cancer treatment. A final analysis was performed after a
median follow-up of approximately 3 years. The 3-year survival rate was lower
(86% vs. 90%; HR 1.42, 95% CI: 0.93, 2.18) and the 3-year relapse-free survival
rate was lower (72% vs. 78%; HR 1.33, 95% CI: 0.99, 1.79) in the darbepoetin
alfa-treated arm compared to the control arm.

Study 4 was a randomized, open-label, controlled study that enrolled 114 of
a planned 460 cervical cancer patients receiving chemotherapy and radiotherapy.
Patients were randomized to receive epoetin alfa to maintain hemoglobin between
12 and 14 g/dL or to RBC transfusion support as needed. The study was terminated
prematurely due to an increase in thromboembolic adverse reactions in epoetin
alfa-treated patients compared to control (19% vs. 9%). Both local recurrence
(21% vs. 20%) and distant recurrence (12% vs. 7%) were more frequent in epoetin
alfa-treated patients compared to control. Progression-free survival at 3 years
was lower in the epoetin alfa-treated group compared to control (59% vs. 62%;
HR 1.06, 95% CI: 0.58, 1.91). Overall survival at 3 years was lower in the epoetin
alfa-treated group compared to control (61% vs. 71%; HR 1.28, 95% CI: 0.68,
2.42).

Hypertension

Epogen is contraindicated in patients with uncontrolled hypertension. Following
initiation and titration of Epogen, approximately 25% of patients on dialysis
required initiation of or increases in antihypertensive therapy; hypertensive encephalopathy and seizures have been reported in patients with CKD receiving
Epogen.

Appropriately control hypertension prior to initiation of and during treatment
with Epogen. Reduce or withhold Epogen if blood pressure becomes difficult to
control. Advise patients of the importance of compliance with antihypertensive
therapy and dietary restrictions [see PATIENT INFORMATION].

Seizures

Epogen increases the risk of seizures in patients with CKD. During the first
several months following initiation of Epogen, monitor patients closely for
premonitory neurologic symptoms. Advise patients to contact their healthcare
practitioner for new-onset seizures, premonitory symptoms or change in seizure
frequency.

Lack or Loss of Hemoglobin Response to Epogen

For lack or loss of hemoglobin response to Epogen, initiate a search for causative
factors (e.g., iron deficiency, infection, inflammation, bleeding). If typical
causes of lack or loss of hemoglobin response are excluded, evaluate for PRCA. In the absence of PRCA, follow dosing
recommendations for management of patients with an insufficient hemoglobin response
to Epogen therapy [see DOSAGE AND ADMINISTRATION].

Pure Red Cell Aplasia

Cases of PRCA and of severe anemia, with or without other cytopenias that arise
following the development of neutralizing antibodies to erythropoietin have
been reported in patients treated with Epogen. This has been reported predominantly
in patients with CKD receiving ESAs by subcutaneous administration. PRCA has
also been reported in patients receiving ESAs for anemia related to hepatitis
C treatment (an indication for which Epogen is not approved).

If severe anemia and low reticulocyte count develop during treatment with Epogen,
withhold Epogen and evaluate patients for neutralizing antibodies to erythropoietin.
Contact Amgen (1-800-77-AMGEN) to perform assays for binding and neutralizing
antibodies. Permanently discontinue Epogen in patients who develop PRCA following
treatment with Epogen or other erythropoietin protein drugs. Do not switch patients
to other ESAs.

Albumin (Human)

Epogen contains albumin, a derivative of human blood [see DESCRIPTION].
Based on effective donor screening and product manufacturing processes, it carries
an extremely remote risk for transmission of viral diseases. A theoretical risk
for transmission of Creutzfeldt-Jakob disease (CJD) also is considered extremely
remote. No cases of transmission of viral diseases or CJD have ever been identified
for albumin.

Dialysis Management

Patients may require adjustments in their dialysis prescriptions after initiation
of Epogen. Patients receiving Epogen may require increased anticoagulation with heparin to prevent clotting of the extracorporeal circuit during hemodialysis.

Laboratory Monitoring

Evaluate transferrin saturation and serum ferritin prior to and during Epogen
treatment. Administer supplemental iron therapy when serum ferritin is less
than 100 mcg/L or when serum transferrin saturation is less than 20% [see DOSAGE
AND ADMINISTRATION]. The majority of patients with CKD will require supplemental
iron during the course of ESA therapy. Following initiation of therapy and after
each dose adjustment, monitor hemoglobin weekly until the hemoglobin level is
stable and sufficient to minimize the need for RBC transfusion.

Patient Counseling Information

Prior to treatment, inform patients of the risks and benefits of Epogen.

Inform patients with cancer that they must sign the patient-healthcare provider
acknowledgment form before the start of each treatment course with Epogen and
that healthcare providers must enroll and comply with the ESA APPRISE Oncology
Program in order to prescribe Epogen.

Inform patients:

To read the Medication Guide and to review and discuss any questions or
concerns with their healthcare provider before starting Epogen and at regular
intervals while receiving Epogen.

Proper disposal of used syringes, needles, and unused vials, and of the
full container.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity

The carcinogenic potential of Epogen has not been evaluated.

Mutagenicity

Epogen was not mutagenic or clastogenic under the conditions tested: Epogen
was negative in the in vitro bacterial reverse mutation assay (Ames test),
in the in vitro mammalian cell gene mutation assay (the hypoxanthine-guanine
phosphoribosyl transferase [HGPRT] locus), in an in vitro chromosomal
aberration assay in mammalian cells, and in the in vivo mouse micronucleus assay.

Impairment of Fertility

When administered intravenously to male and female rats prior to and during
mating, and to females through the beginning of implantation (up to gestational
day 7; dosing stopped prior to the beginning of organogenesis), doses of 100
and 500 Units/kg/day of Epogen caused slight increases in pre-implantation loss,
post-implantation loss and decreases in the incidence of live fetuses. It is
not clear whether these effects reflect a drug effect on the uterine environment
or on the conceptus. This animal dose level of 100 Units/kg/day approximates
the clinical recommended starting dose, depending on the patient's treatment
indication, but may be lower than the clinical dose in patients whose doses
have been adjusted.

Use In Specific Populations

Pregnancy

The multidose vials are formulated with benzyl alcohol. Do not administer Epogen
from multidose vials, or Epogen from single-dose vials admixed with bacteriostatic saline containing benzyl alcohol, to pregnant women. When therapy with Epogen
is needed during pregnancy, use a benzyl alcohol-free formulation [see DOSAGE
AND ADMINISTRATION and CONTRAINDICATIONS].

Pregnancy Category C (single-dose vials only)

There are no adequate and well-controlled studies of Epogen use during pregnancy.
There are limited data on Epogen use in pregnant women. In animal reproductive
and developmental toxicity studies, adverse fetal effects occurred when pregnant
rats received epoetin alfa at doses approximating the clinical recommended starting
doses. Single-dose formulations of Epogen should be used during pregnancy only
if the potential benefit justifies the potential risk to the fetus.

There are reports of at least 33 pregnant women with anemia alone or anemia
associated with severe renal disease and other hematologic disorders who received
Epogen. Polyhydramnios and intrauterine growth restriction were reported in
women with chronic renal disease, which is associated with an increased risk
for these adverse pregnancy outcomes. There was 1 infant born with pectus excavatum
and hypospadias following exposure during the first trimester. Due to the limited
number of exposed pregnancies and multiple confounding factors (such as underlying
maternal conditions, other maternal medications, and gestational timing of exposure),
these published case reports and studies do not reliably estimate the frequency
or absence of adverse outcomes.

When healthy rats received Epogen at doses of 100 Units/kg/day during mating
and through early pregnancy (dosing stopped prior to organogenesis), there were
slight increases in the incidences of pre-and post-implantation loss, and a
decrease in live fetuses. This animal dose level of 100 Units/kg/day may approximate
the clinical recommended starting dose, depending on the treatment indication.
When healthy pregnant rats and rabbits received intravenous doses of up to 500
mg/kg/day of Epogen only during organogenesis, no teratogenic effects were observed
in the offspring.

When healthy pregnant rats received Epogen at doses of 500 Units/kg/day late
in pregnancy (after the period of organogenesis), offspring had decreased number
of caudal vertebrae and growth delays [see Nonclinical Toxicology].

Women who become pregnant during Epogen treatment are encouraged to enroll
in Amgen's Pregnancy Surveillance Program. Patients or their physicians should
call 1-800-772-6436 (1-800-77-AMGEN) to enroll.

Nursing Mothers

The multidose vials of Epogen are formulated with benzyl alcohol. Do not administer
Epogen from multidose vials, or Epogen from single-dose vials admixed with bacteriostatic
saline containing benzyl alcohol, to a nursing woman. When therapy with Epogen
is needed in nursing women, use a benzyl alcohol-free formulation [see DOSAGE
AND ADMINISTRATION and CONTRAINDICATIONS].

It is not known whether Epogen is excreted in human milk. Because many drugs
are excreted in human milk, caution should be exercised when Epogen from single-dose
vials is administered to a nursing woman.

Pediatric Use

The multidose vials are formulated with benzyl alcohol. Do not administer Epogen
from multidose vials, or Epogen from single-dose vials admixed with bacteriostatic
saline containing benzyl alcohol, to neonates or infants. When therapy with
Epogen is needed in neonates and infants, use a benzyl alcohol-free formulation
[see DOSAGE AND ADMINISTRATION and CONTRAINDICATIONS].

Benzyl alcohol has been associated with serious adverse events and death, particularly
in pediatric patients. The “gasping syndrome,” (characterized by
central nervous system depression, metabolicacidosis, gasping respirations,
and high levels of benzyl alcohol and its metabolites found in the blood and
urine) has been associated with benzyl alcohol dosages > 99 mg/kg/day in
neonates and low-birthweight neonates. Additional symptoms may include gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities,
skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular
collapse.

Although normal therapeutic doses of this product deliver amounts of benzyl
alcohol that are substantially lower than those reported in association with
the “gasping syndrome”, the minimum amount of benzyl alcohol at
which toxicity may occur is not known. Premature and low-birthweight infants,
as well as patients receiving high dosages, may be more likely to develop toxicity.
Practitioners administering this and other medications containing benzyl alcohol
should consider the combined daily metabolic load of benzyl alcohol from all
sources.

Pediatric Patients on Dialysis

Epogen is indicated in pediatric patients, ages 1 month to 16 years of age,
for the treatment of anemia associated with CKD requiring dialysis. Safety and
effectiveness in pediatric patients less than 1 month old have not been established
[see Clinical Studies].

The safety data from these studies are similar to those obtained from the studies
of Epogen in adult patients with CKD [see WARNINGS AND PRECAUTIONS and
ADVERSE REACTIONS].

Pediatric Cancer Patients on Chemotherapy

Epogen is indicated in patients 5 to 18 years old for the treatment of anemia
due to concomitant myelosuppressive chemotherapy. Safety and effectiveness in
pediatric patients less than 5 years of age have not been established [see Clinical
Studies]. The safety data from these studies are similar to those obtained
from the studies of Epogen in adult patients with cancer [see WARNINGS AND
PRECAUTIONS and ADVERSE REACTIONS].

Pediatric Patients With HIV Infection Receiving Zidovudine

Published literature has reported the use of Epogen in 20 zidovudine-treated,
anemic, pediatric patients with HIV infection, ages 8 months to 17 years, treated
with 50 to 400 Units/kg subcutaneously or intravenously 2 to 3 times per week.
Increases in hemoglobin levels and in reticulocyte counts and decreases in or
elimination of RBC transfusions were observed.

Pharmacokinetics in Neonates

Limited pharmacokinetic data from a study of 7 preterm, very low birth weight
neonates and 10 healthy adults given intravenous erythropoietin suggested that
distribution volume was approximately 1.5 to 2 times higher in the preterm neonates
than in the healthy adults, and clearance was approximately 3 times higher in
the preterm neonates than in the healthy adults.

Geriatric Use

Of the 4553 patients who received Epogen in the 6 studies for treatment of
anemia due to CKD not receiving dialysis, 2726 (60%) were age 65 years and over,
while 1418 (31%) were 75 years and over. Of the 757 patients who received Epogen
in the 3 studies of CKD patients on dialysis, 361 (47%) were age 65 years and
over, while 100 (13%) were 75 years and over. No differences in safety or effectiveness
were observed between geriatric and younger patients. Dose selection and adjustment
for an elderly patient should be individualized to achieve and maintain the
target hemoglobin [see DOSAGE AND ADMINISTRATION].

Among 778 patients enrolled in the 3 clinical studies of Epogen for the treatment
of anemia due to concomitant chemotherapy, 419 received Epogen and 359 received
placebo. Of the 419 who received Epogen, 247 (59%) were age 65 years and over,
while 78 (19%) were 75 years and over. No overall differences in safety or effectiveness
were observed between geriatric and younger patients. The dose requirements
for Epogen in geriatric and younger patients within the 3 studies were similar.

Among 1731 patients enrolled in the 6 clinical studies of Epogen for reduction
of allogeneic RBC transfusions in patients undergoing elective surgery, 1085
received Epogen and 646 received placebo or standard of care treatment. Of the
1085 patients who received Epogen, 582 (54%) were age 65 years and over, while
245 (23%) were 75 years and over. No overall differences in safety or effectiveness
were observed between geriatric and younger patients. The dose requirements
for Epogen in geriatric and younger patients within the 4 studies using the
3 times weekly schedule and 2 studies using the weekly schedule were similar.

Insufficient numbers of patients age 65 years or older were enrolled in clinical
studies of Epogen for the treatment of zidovudine in HIV-infected patients to
determine whether they respond differently from younger patients.

Last reviewed on RxList: 6/20/2012
This monograph has been modified to include the generic and brand name in many instances.